Progressive and chronic airway inflammation and infection are hallmarks of cystic fibrosis (CF) lung disease. A reduction of the host inflammatory response could favorably modify the disease phenotype. Indeed this has been the goal of clinical trials with steroids and non-steroidal anti-inflammatory drugs. Another approach to reduce inflammation is to silence pro-inflammatory mediators by RNA interference (RNAi). Here, we propose to use several novel methods to accomplish RNAi in the airways. In one approach, we hypothesize that virally expressed inhibitory RNAs can effectively transduce airway epithelia and inhibit expression of our target genes. We will use methods developed in our laboratories for optimal inhibitory RNA expression. In a second approach, we will use peptide-siRNA complexes. In these experiments, we will take advantage of peptides that bind to airway epithelia to direct siRNA uptake and target gene silencing. For both viral and nonviral experiments, we will first test the effectiveness in vitro using well differentiated airway epithelia. Once optimized in vitro, the tools will be tested in vivo in wild type, and then CF pigs. Importantly, the methods we develop to deliver RNAi and reduce geneexpression in vitro and in vivo will have direct relevance to other pro-inflammatory targets, and newly identified participants in CF ainway disease.